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Studying the Unfolding Kinetics of Proteins under Pressure Using Long Molecular Dynamic Simulation Runs

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Abstract

The usefulness of computational methods such as molecular dynamics simulation has been extensively established for studying systems in equilibrium. Nevertheless, its application to complex non-equilibrium biological processes such as protein unfolding has been generally regarded as producing results which cannot be interpreted straightforwardly. In the present study, we present results for the kinetics of unfolding of apomyoglobin, based on the analysis of long simulation runs of this protein in solution at 3 kbar (1 atm = 1.01325, bar = 101 325 Pa). We hereby demonstrate that the analysis of the data collected within a simulated time span of 0.18 μs suffices for producing results, which coincide remarkably with the available unfolding kinetics experimental data. This not only validates molecular dynamics simulation as a valuable alternative for studying non-equilibrium processes, but also enables a detailed analysis of the actual structural mechanism which underlies the unfolding process of proteins under elusive denaturing conditions such as high pressure.

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References

  1. Damjanović, A., García-Moreno, B., Lattman, E.E., García, A.E.: Molecular dynamics study of water penetration in staphylococcal nuclease. Proteins 60, 433–449 (2005)

    Article  Google Scholar 

  2. Mohan, G., Kopelevich, D.I.: A multiscale model for kinetics of formation and disintegration of spherical micelles. J. Chem. Phys. 128, 044905 (2008)

    Article  ADS  Google Scholar 

  3. Sriraman, S., Kevrekidis, I.G., Hummer, G.: Coarse nonlinear dynamics and metastability of filling-emptying transitions: water in carbon nanotubes. Phys. Rev. Lett. 95, 130603 (2005)

    Article  ADS  Google Scholar 

  4. Seibert, M.M., Patriksson, A., Hess, B., van der Spoel, D.: Reproducible polypeptide folding and structure prediction using molecular dynamics simulations. J. Mol. Biol. 354, 173–83 (2005)

    Article  Google Scholar 

  5. van der Spoel, D., Seibert, M.M.: Protein folding kinetics and thermodynamics from atomistic simulations. Phys. Rev. Lett. 96, 238102 (2006)

    Article  ADS  Google Scholar 

  6. Prakash, S., Matouschek, A.: Protein unfolding in the cell. Trends Biochem. Sci. 29, 593–600 (2004)

    Article  Google Scholar 

  7. Scheraga, H.A., Khalili, M., Liwo, A.: Protein-folding dynamics: overview of molecular simulation techniques. Annu. Rev. Phys. Chem. 58, 57–83 (2007)

    Article  Google Scholar 

  8. Jamin, M., Yeh, S., Rousseau, D.L., Baldwin, R.L.: Submillisecond unfolding kinetics of apomyoglobin and its pH 4 intermediate. J. Mol. Biol. 292, 731–740 (1999)

    Article  Google Scholar 

  9. McCarthy, A.N., Grigera, J.R.: Pressure denaturation of apomyoglobin: a molecular dynamics simulation study. Biochim. Biophys. Acta. 1764, 506–515 (2006)

    Google Scholar 

  10. Eliezer, D., Yao, J., Dyson, H.J., Wright, P.E.: Structural and dynamic characterization of partially folded states of apomyoglobin and implications for protein folding. Nat. Struct. Biol. 5, 148–155 (1998)

    Article  Google Scholar 

  11. Kitahara, R., Yamada, H., Akasaka, K., Wright, P.E.: High pressure NMR reveals that apomyoglobin is an equilibrium mixture from the native to the unfolded. J. Mol. Biol. 320, 311–319 (2002)

    Article  Google Scholar 

  12. Creamer, T.P., Srinivasan, R., Rose, G.D.: Modeling unfolded states of proteins and peptides. II. Backbone solvent accessibility. Biochemistry 36, 2832–2835 (1997)

    Article  Google Scholar 

  13. Geierhaas, C.D., Nickson, A.A., Lindorff-Larsen, K., Clarke, J., Vendruscolo, M.: BPPred: a Web-based computational tool for predicting biophysical parameters of proteins. Protein Sci. 16, 125–134 (2007)

    Article  Google Scholar 

  14. Myers, J.K., Pace, C.N., Scholtz, J.M.: Denaturant m values and heat capacity changes: relation to changes in accessible surface areas of protein unfolding. Protein Sci. 4, 2138–2148 (1995)

    Article  Google Scholar 

  15. Schellman, J.A.: Solvent denaturation. Biopolymers 17, 1305–1322 (1978)

    Article  Google Scholar 

  16. Berendsen, H.J.C., van der Spoel, D., van Drunen, R.: GROMACS: a message-passing parallel molecular dynamics implementation. Comput. Phys. Commun. 91, 43–56 (1995)

    Article  ADS  Google Scholar 

  17. Lindahl, E., Hess, B., van der Spoel, D.: Gromacs 3.0: a package for molecular simulation and trajectory analysis. J. Molecular Modeling 7, 306–317 (2001)

    Google Scholar 

  18. van Gunsteren, W.F., Berendsen, H.J.C.: Computer simulation of molecular dynamics: methodology, applications, and perspectives in chemistry. Angew. Chem. Int. Ed. Engl. 29, 992–1023 (1990)

    Article  Google Scholar 

  19. Jorgensen, W.L., Chandrasekhar, J., Madura, J.D., Impey, R.W., Klein, M.L.: Comparison of simple potential functions for simulating liquid water. J. Chem. Phys. 79, 926–935 (1983)

    Article  ADS  Google Scholar 

  20. Liu, H., Müller-Plathe, F., van Gunsteren, W.F.: A force field for liquid dimethyl sulfoxide and liquid properties of liquid dimethyl sulfoxide calculated using molecular dynamics simulation. J. Am. Chem. Soc. 117, 4363–4366 (1995)

    Article  Google Scholar 

  21. Mark, A.E., van Helden, S.P., Smith, P.E., Janssen, L.H.M., van Gunsteren, W.F.: Convergence properties of free energy calculations: cyclodextrin complexes as a case study. J. Am. Chem. Soc. 116, 6293–6302 (1994)

    Article  Google Scholar 

  22. van Buuren, A.R., Berendsen, H.J.C.: Molecular dynamics simulation of the stability of a 22 residue alpha-helix in water and 30% trifluoroethanol. Biopolymers 33, 1159–1166 (1993)

    Article  Google Scholar 

  23. van Buuren, A.R., Marrink, S.J., Berendsen, H.J.C.: A molecular dynamics study of the decane/water interface. J. Phys. Chem. 97, 9206–9212 (1993)

    Article  Google Scholar 

  24. van Gunsteren, W.F., Berendsen, H.J.C.: Gromos-87 manual. Biomos BV Nijenborgh, vol. 4, p. 9747. AG Groningen, The Netherlands (1987)

    Google Scholar 

  25. Hess, B., Bekker, H., Berendsen, H.J.C., Fraaije, J.G.E.M.: LINCS: a linear constraint solver for molecular simulations. J. Comput. Chem. 18, 1463–1472 (1997)

    Article  Google Scholar 

  26. Miyamoto, S., Kollman, P.A.: SETTLE An analytical version of the SHAKE and RATTLE algorithms for rigid water models. J. Comput. Chem. 13, 952–962 (1992)

    Article  Google Scholar 

  27. Berendsen, H.J.C., Grigera, J.R., Straatsma, T.P.: The missing term in effective pair potentials. J. Chem. Phys. 91, 6269–6271 (1987)

    Article  Google Scholar 

  28. Berendsen, H.J.C., Postma, J.P.M., DiNola, A., Haak, J.R.: Molecular dynamics with coupling to an external bath. J. Chem. Phys. 81, 3684–3690 (1984)

    Article  ADS  Google Scholar 

  29. van der Spoel, D., Lindahl, E., Hess, B., van Buuren, A.R., Apol, E., Meulenhoff, P.J., Tieleman, D.P., Sijbers, A.L.T.M., Feenstra, K.A., van Drunen, R., Berendsen, H.J.C.: Gromacs user manual version 3.2, www.gromacs.org (2004)

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Authors and Affiliations

  1. Instituto de Física de Líquidos y Sistemas Biológicos, CCT La Plata CONICET, UNLP, CIC, La Plata, Argentina

    Osvaldo Chara, José Raúl Grigera & Andrés N. McCarthy

  2. Departamento de Fisiología y Biofísica, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina

    Osvaldo Chara

  3. Departamento de Ciencias Biológicas, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, 49-789, cc 565, B1900BTE, La Plata, Argentina

    José Raúl Grigera & Andrés N. McCarthy

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  1. Osvaldo Chara
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  2. José Raúl Grigera
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  3. Andrés N. McCarthy
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Correspondence to Andrés N. McCarthy.

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Chara, O., Grigera, J.R. & McCarthy, A.N. Studying the Unfolding Kinetics of Proteins under Pressure Using Long Molecular Dynamic Simulation Runs. J Biol Phys 33, 515–522 (2007). https://doi.org/10.1007/s10867-008-9083-2

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  • DOI: https://doi.org/10.1007/s10867-008-9083-2

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